Researchers breathe life into exhausted T cells in a study on page 2763.

HIV beats the immune system in part because killer T cells stop fighting the virus. PD-1, a T cell inhibitory protein that normally prevents over-inflammation, was recently associated with chronic HIV. Now Jones et al. identify another manipulated manager, TIM-3.

When CD4+ T cells express the glycoprotein TIM-3, proliferation and cytokine production are suppressed. Because disruption of TIM-3 is known to induce hyperactive inflammatory responses, as seen in autoimmune diseases like multiple sclerosis, Jones et al. predicted that the opposite might be true in HIV infection. The team assessed T cells from HIV patients and found that high levels of the protein indeed corresponded to a heavy viral load.

TIM-3–expressing CD4+ and CD8+ T cells from HIV-infected patients secreted far less interferon (IFN)-γ and TNF than did cells without TIM-3. And blocking TIM-3's ligand reversed this effect. Although the effect of blocking TIM-3 and PD-1 is similar, these molecules were found on distinct populations of CD8+ T cells.

Half of the participants undergoing antiretroviral therapy maintained high TIM-3 expression, even after their viral loads diminished, suggesting to the authors that TIM-3 upregulation may be irreversible in some individuals. And obstructing its signals could be an important means of controlling the underlying virus that persists despite therapy.

Many of the steps between the virus and TIM-3 manipulation aren't yet known, and it appears that HIV isn't the only T cell exhauster. Learning how to revive tired cells might therefore help patients with other chronic infections as well. AM